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MANUFACTURING OPERATIONS AND CONTROLS

Charge-in of components:

Written production and control procedures shall include the following,

which are designed to assure that the drug products produced have the
identity, strength, quality, and purity they purport or are represented to
possess:
(a) The batch shall be formulated with the intent to provide not less than
100 percent of the labeled or established amount of active ingredient.
(b) Components for drug product manufacturing shall be weighed,
measured, or subdivided as appropriate. If a component is removed from
the original container to another, the new container shall be identified
with the following information:
(1) Component name or item code,
(2) Receiving or control number,
(3) Weight or measure in new container, and
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components shall
be adequately supervised. Each container of component dispensed to
manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit,
(2) The weight or measure is correct as stated in the batch production
records,
(3) The containers are properly identified. If the weighing, measuring,
or subdividing operations are performed by automated equipment
under 211.68,only one person is needed to assure of this section.
(d) Each component shall either be added to the batch by one person and
verified by a second person or, if the components are added by automated
equipment under 211.68, only verified by one person.

Automatic, mechanical, and electronic equipment(211.68)

(a) Automatic, mechanical, or electronic equipment or other types of

equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing, packing,
and holding of a drug product. If such equipment is so used, it shall be
routinely calibrated, inspected, or checked according to a written program
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designed to assure proper performance. Written records of those calibration

checks and inspections shall be maintained.

(b) Appropriate controls shall be exercised over computer or related systems to

assure that changes in master production and control records or other records
are instituted only by authorized personnel. Input to and output from the
computer or related system of formulas or other records or data shall be
checked for accuracy. The degree and frequency of input/output verification
shall be based on the complexity and reliability of the computer or related
system. A backup file of data entered into the computer or related system shall
be maintained except where certain data, such as calculations performed in
connection with laboratory analysis, are eliminated by computerization or other
automated processes. In such instances a written record of the program shall
be maintained along with appropriate validation data. Hard copy or alternative
systems, such as duplicates, tapes, or microfilm, designed to assure that
backup data are exact and complete and that it is secure from alteration,
inadvertent erasures, or loss shall be maintained.

Time limitations on production:

When appropriate, time limits for the completion of each phase of

production shall be established to assure the quality of the drug product.
Deviation from established time limits may be acceptable if such
deviation does not compromise the quality of the drug product. Such
deviation shall be justified and documented.

Time limits should include, for example, the period between the start of bulk
product compounding and its sterilization, filtration processes, product
exposure while on the processing line, and storage of sterilized equipment,
containers and closures.
The total time for product filtration should be limited to an established
maximum to prevent microorganisms from penetrating the filter. Such a time
limit should also prevent a significant increase in upstream bioburden and
endotoxin load

Deviations:-

(a) There shall be written procedures for production and process control
designed to assure that the drug products have the identity, strength, quality,
and purity they purport or are represented to possess. Such procedures shall
include all requirements in this subpart. These written procedures, including
any changes, shall be drafted, reviewed, and approved by the appropriate
organizational units and reviewed and approved by the quality control unit.

(b) Written production and process control procedures shall be followed in the
execution of the various production and process control functions and shall be
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documented at the time of performance. Any deviation from the written

procedures shall be recorded and justified.

Drug product inspection:

(a) Packaged and labeled products shall be examined during finishing

operations to provide assurance that containers and packages in the lot have
the correct label.

(b) A representative sample of units shall be collected at the completion of

finishing operations and shall be visually examined for correct labeling.

(c) Results of these examinations shall be recorded in the batch production or

control records.

Expiry date calculation:

(a)To assure that a drug product meets applicable standards of identity,

strength, quality, and purity at the time of use, it shall bear an expiration date
determined by appropriate stability testing.
(b) Expiration dates shall be related to any storage conditions stated on the
labeling, as determined by stability studies.
(c) If the drug product is to be reconstituted at the time of dispensing, its
labeling shall bear expiration information for both the reconstituted and
unreconstituted drug products.
(d) Expiration dates shall appear on labeling in accordance with the
requirement of location of expiration date i.e as follows:-

When an expiration date of a drug is required it shall appear on the immediate

container and also the outer package, if any, unless it is easily legible through
such outer package. However, when single-dose containers are packed in
individual cartons, the expiration date may properly appear on the individual
carton instead of the immediate product container.

(e) Homeopathic drug products shall be exempt from the requirements of this
section.
(f) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt
from the requirements of this section.
(g) New drug products for investigational use are exempt from the requirements
of this section, provided that they meet appropriate standards or specifications
as demonstrated by stability studies during their use in clinical investigations.
Where new drug products for investigational use are to be reconstituted at the
time of dispensing, their labeling shall bear expiration information for the
reconstituted drug product.

(h) Pending consideration of a proposed exemption, published in the FEDERAL

REGISTER of September 29, 1978, the requirements in this section shall not be
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enforced for human OTC drug products if their labeling does not bear dosage
limitations and they are stable for at least 3 years as supported by appropriate
stability data.

Stability testing:-

(a) There shall be a written testing program designed to assess the stability
characteristics of drug products. The results of such stability testing shall be
used in determining appropriate storage conditions and expiration dates. The
written program shall be followed and shall include:

(1) Sample size and test intervals based on statistical criteria for each attribute
examined to assure valid estimates of stability,
(2) Storage conditions for samples retained for testing,
(3) Reliable, meaningful, and specific test methods,
(4) Testing of the drug product in the same container-closure system as that in
which the drug product is marketed, and
(5) Testing of drug products for reconstitution at the time of dispensing (as
directed in the labeling) as well as after they are reconstituted.

(b) An adequate number of batches of each drug product shall be tested to

determine an appropriate expiration date and a record of such data shall be
maintained. Accelerated studies, combined with basic stability information on
the components, drug products, and container-closure system, may be used to
support tentative expiration dates provided full shelf life studies are not
available and are being conducted. Where data from accelerated studies are
used to project a tentative expiration date that is beyond a date supported by
actual shelf life studies, there must be stability studies conducted, including
drug product testing at appropriate intervals, until the tentative expiration date
is verified or the appropriate expiration date determined.

(c) For homeopathic drug products, the requirements of this section are as
follows:

(1) There shall be a written assessment of stability based at least on testing or

examination of the drug product for compatibility of the ingredients, and based
on marketing experience with the drug product to indicate that there is no
degradation of the product for the normal or expected period of use.
(2) Evaluation of stability shall be based on the same container-closure system
in which the drug product is being marketed.

(d) Allergenic extracts that are labeled “No U.S. Standard of Potency” are
exempt from the requirements of this section.
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Calculation of yield:

Actual yields and percentages of theoretical yield shall be determined at the

conclusion of each appropriate phase of manufacturing, processing, packaging,
or holding of the drug product. Such calculations shall either be performed by
one person and independently verified by a second person, or, if the yield is
calculated by automated equipment under 211.68, be independently verified by
one person.

Production record review:

 All drug product production and control records, including those for
packaging and labeling, shall be reviewed and approved by the quality
control unit to determine compliance with all established, approved
written procedures before a batch is released or distributed.
 Any unexplained discrepancy (including a percentage of theoretical yield
exceeding the maximum or minimum percentages established in master
production and control records) or the failure of a batch or any of its
components to meet any of its specifications shall be thoroughly
investigated, whether or not the batch has already been distributed.
 The investigation shall extend to other batches of the same drug product
and other drug products that may have been associated with the specific
failure or discrepancy.
 A written record of the investigation shall be made and shall include the
conclusions and follow up.

Master production and control records:-

(a) To assure uniformity from batch to batch, master production and control
records for each drug product, including each batch size thereof, shall be
prepared, dated, and signed (full signature, handwritten) by one person and
independently checked, dated, and signed by a second person. The preparation
of master production and control records shall be described in a written
procedure and such written procedure shall be followed.

(b) Master production and control records shall include:

(1) The name and strength of the product and a description of the dosage form,
(2) The name and weight or measure of each active ingredient per dosage unit
or per unit of weight or measure of the drug product, and a statement of the
total weight or measure of any dosage unit,
(3) A complete list of components designated by names or codes sufficiently
specific to indicate any special quality characteristic,
(4) An accurate statement of the weight or measure of each component, using
the same weight system (metric, avoirdupois, or apothecary) for each
component. Reasonable variations may be permitted, however, in the amount
of components necessary for the preparation in the dosage form, provided they
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are justified in the master production and control records,

(5) A statement concerning any calculated excess of component,
(6) A statement of theoretical weight or measure at appropriate phases of
processing,
(7) A statement of theoretical yield, including the maximum and minimum
percentages of theoretical yield beyond which investigation according to
production records.

(8) A description of the drug product containers, closures, and packaging

materials, including a specimen or copy of each label and all other labeling
signed and dated by the person or persons responsible for approval of such
labeling, and
(9) Complete manufacturing and control instructions, sampling and testing
procedures, specifications, special notations, and precautions to be followed.

Batch production and control records:-

Batch production and control records shall be prepared for each batch of drug
product produced and shall include complete information relating to the
production and control of each batch. These records shall include:

(a) An accurate reproduction of the appropriate master production or control

record, checked for accuracy, dated, and signed,

(b) Documentation that each significant step in the manufacture, processing,

packing, or holding of the batch was accomplished, including:

(1) Dates,
(2) Identity of individual major equipment and lines used,
(3) Specific identification of each batch of component or in-process material
used,
(4) Weights and measures of components used in the course of processing,
(5) In-process and laboratory control results,
(6) Inspection of the packaging and labeling area before and after use,
(7) A statement of the actual yield and a statement of the percentage of
theoretical yield at appropriate phases of processing,
(8) Complete labeling control records, including specimens or copies of all
labeling used,
(9) Description of drug product containers and closures,
(10) Any sampling performed;
(11) Identification of the persons performing and directly supervising or
checking each significant step in the operation, or if a significant step in the
operation is performed by automated equipment under §211.68, the
identification of the person checking the significant step performed by the
automated equipment,
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(12) Any investigation made according toproduction record review,

(13) Results of examinations made in accordance with drug product inspection.

Packaging and labeling operations.

There shall be written procedures designed to assure that correct labels,

labeling, and packaging materials are used for drug products; such written
procedures shall be followed. These procedures shall incorporate the following
features:

(a) Prevention of mixups and cross-contamination by physical or spatial

separation from operations on other drug products.

(b) Identification and handling of filled drug product containers that are set
aside and held in unlabeled condition for future labeling operations to preclude
mislabeling of individual containers, lots, or portions of lots. Identification need
not be applied to each individual container but shall be sufficient to determine
name, strength, quantity of contents, and lot or control number of each
container.

(c) Identification of the drug product with a lot or control number that
permits determination of the history of the manufacture and control of the
batch.

(d) Examination of packaging and labeling materials for suitability and

correctness before packaging operations, and documentation of such
examination in the batch production record.

(e) Inspection of the packaging and labeling facilities immediately before

use to assure that all drug products have been removed from previous
operations. Inspection shall also be made to assure that packaging and
labeling materials not suitable for subsequent operations have been removed.
Results of inspection shall be documented in the batch production records.

Change Control Procedure:-

Change control is a CGMP concept that focuses on managing change to prevent

unintended consequences sometimes encountered when making a change to a
product or system. • Change control is not department-specific, rather the task
of the whole company. Manufacturers certified to ISO 9000:2000 and ISO
13485 standards are required to ensure that any changes.
 Certain manufacturing changes (i.e changes that alter specifications, a
critical product attribute or bioavailability) require regulatory filings and
prior regulatory approval. Change is an inherent part of the life cycle of a
pharmaceutical product. A change can be an addition to, deletion of, or
modification to manufacturing facility, utilities, process, material,
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product, procedures or equipment.(including software) which impacts

quality or regulatory requirements.
 Change control is a procedure that ensures changes are implemented in
a controlled and coordinated manner. The change control program
evaluate all changes that could affect the production and control of the
drug product, intermediate or API.
 It is the most critical element in the overall quality management of
pharmaceutical industry. A change control system provides checks and
balances in the quality system by tracking, reviewing and approving the
changes. In adequate change control procedures ends up in regulatory
non compliance.

Benefits of change control system:

 Structured and systematic approach for change management with proper

change evaluation
 Documenting & tracking the details of change
 Routing of change requests to appropriate individuals/team for approvals
 Demonstrate compliance to regulatory agencies

Change control Process flow: Changes can happen anytime during a

product’s life cycle. Steps as follows

1. Change proposal

2. Change Evaluation/review

3. Change Classification

4. Identification of impacted systems/documents & risk assessment

5. Change Approval
6. Change implementation

7. Verification of change implementation

8. Change control close out

Change control Procedure:

 A formal change control procedure always begins with a change proposal,
which is initiated by user department personnel with proper justification.
Initiator Change is typically introduced by a initiator or originator.
Initiating a changes involves filling out a change request form which
them moves through a process or system of review and approval.
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 The change proposal then, evaluated by an expert team (change control

committee) contributing the appropriate expertise and knowledge from
relevant areas.
 After change evaluation, quality unit will classify the change (i.e
minor/major/critical).Benefits of change classification includes
 Classification can help in assessing the impact of change in a reliable
way.
 Change classification can be used to identify risk associated with each
change request.
 Change classification can help to determine the change acceptability (i.e
reject or approve changes). • A classification procedure may help in
determining the level of testing, validation and documentation needed to
justify the changes of validated process. • They can also be categorized
as specification changes, raw material changes, equipment changes.
 Change classification triggers impact analysis of the proposed change for
identification of impacted systems and documents. There are several risk
associated with each change proposal, including reduced product
quality. Risk assessment in changing requirements of existing systems is
an important aspect of producing the desired result of a change.
 EXAMPLES: • Changes of manufacturers, other synthesis route of a
starting material (other impurities) • Removal of processes to other site •
Change in the product composition • Change to the process parameters.
• Replacement of apparatus part of the same design • Change of cleaning
agent for floors • Change of laundry for work clothes (non-sterile or
antibiotics area) • Change to working times • Installation of air
conditioner in administrative area • Change in purchase procedure
 After impact analysis and risk reduction, quality unit will approve or
reject the change proposal based on the criticality of the proposed
change.
 The change can be implemented after change approval by quality unit.
After implementation, quality unit verify the effectiveness of implemented
changes, to confirm the change objectives were achieved and that there
was no deleterious impact on product quality.
 After verification of change implementation, the change control can be
closed. Three primary tasks at this end phase include determining that
the project is actually complete, evaluating "the project plan in the
context of project completion," and providing tangible proof of project
success.

Change control procedure should ensure that the level of documentation and
effort is matched to the risk associated with the change. It should be ensured
that

Includes criteria to evaluate whether changes affects regulatory filings.

Includes evaluation criteria for determining if changes are technically justified.

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GMP deficiencies related to change control:

 Inadequate review & approval of the change by quality control unit.
 Failure to file the changes with regulatory.
 Failure to evaluate/justify the changes.
 Excluding "like-for-like" changes from change control program.

Sterile products and aseptic process control:-

"Sterile products" refers to products that are going to be administered using

an enteral route of administration. The "products" are going to be infused
directly into the bloodstream or body tissue, it is extremely important they be
"sterile".
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Aseptic process control:

Aseptic Processing is the production of sterile drug products by bringing

together the product, container, and closure that have been subjected to
different sterilization methods separately, and assembled them in an extremely
high quality environment by skilled personnel using the right tools.

There are basic differences between the production of sterile drug products
using aseptic processing and production using terminal sterilization.

Terminal sterilization:
 Usually involves filling and sealing product containers under high-quality
environmental conditions. Products are filled and sealed in this type of
environment to minimize the microbial and particulate content of the in-
process product and to help ensure that the subsequent sterilization
process is successful. In most cases, the product, container, and closure
have low bioburden, but they are not sterile.
 The product in its final container is then subjected to a sterilization
process such as heat or irradiation.

Aseptic process:
 The drug product, container, and closure are first subjected to
sterilization methods separately, as appropriate, and then brought
together.Because there is no process to sterilize the product in its final
container, it is critical that containers be filled and sealed in an
extremely high-quality environment. Aseptic processing involves more
variables than terminal sterilization.
 Before aseptic assembly into a final product, the individual parts of the
final product are generally subjected to various sterilization processes.
For example:- Glass containers are subjected to dry heat;
Rubber closures are subjected to moist heat; and liquid dosage forms
are subjected to filtration.
 Each of these manufacturing processes requires validation and control.
Each process could introduce an error that ultimately could lead to the
distribution of a contaminated product. Any manual or mechanical
manipulation of the sterilized drug, components, containers, or closures
prior to or during aseptic assembly poses the risk of contamination and
thus necessitates careful control.
 A terminally sterilized drug product, on the other hand, undergoes final
sterilization in a sealed container, thus limiting the possibility of error.

Regulations:

Aseptic processing, which includes as appropriate:

(i) Floors, walls, and ceilings of smooth, hard surfaces that are easily
cleanable,
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(ii) Temperature and humidity controls,

(iii) An air supply filtered through high-efficiency particulate air filters
under positive pressure, regardless of whether flow is laminar or
nonlaminar,
(iv) A system for monitoring environmental conditions,
(v) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions, and
(vi) A system for maintaining any equipment used to control the aseptic
conditions.
(vii) Equipment for adequate control over air pressure, micro-organisms,
dust, humidity, and temperature shall be provided when appropriate for
the manufacture, processing, packing, or holding of a drug product.

 21 CFR 211.46(c) states, that Air filtration systems, including prefilters

and particulate matter air filters, shall be used when appropriate on air
supplies to production areas.
 21 CFR 211.63 states that “Equipment used in the manufacture,
processing, packing, or holding of a drug product shall be of appropriate
design, adequate size, and suitably located to facilitate operations for its
intended use and for its cleaning and maintenance.”
 21 CFR 211.65(a) states that “Equipment shall be constructed so that
surfaces that contact components, in-process materials, or drug
products shall not be reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the drug product beyond
the official or other established requirements.”
 21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned,
maintained, and sanitized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.”
 21 CFR 211.113(b) states that “Appropriate written procedures, designed
to prevent microbiological contamination of drug products purporting to
be sterile, shall be established and followed. Such procedures shall
include validation of any sterilization process.”

1.Clean area:

Clean area control parameters should be supported by microbiological and

particle data obtained during qualification studies. Initial clean room
qualification includes, in part, an assessment of air quality under as-built,
static conditions. It is important for area qualification and classification to
place most emphasis on data generated under dynamic conditions (i.e., with
personnel present, equipment in place, and operations ongoing). An adequate
aseptic processing facility monitoring program also will assess conformance
with specified clean area classifications under dynamic conditions on a routine
basis.
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Clean Area > 0.5 μm Microbiological Microbiological

Classification particles/m3 Active Air Settling Plates
(0.5 um Action Levelsc Action
particles/ft3) (cfu/m3 ) Levelsc,d
(diam. 90mm;
cfu/4 hours)

100 3520 1 1
1000 35200 7 3
10000 352000 10 5
100000 3520000 100 50

Critical Area – Class 100

A critical area is one in which the sterilized drug product, containers, and
closures are exposed to environmental conditions that must be designed to
maintain product sterility. Activities conducted in such areas include
manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile
materials prior to and during filling and closing operations.

This area is critical because an exposed product is vulnerable to contamination

and will not be subsequently sterilized in its immediate container. To maintain
product sterility, it is essential that the environment in which aseptic
operations (e.g., equipment setup, filling) are conducted be controlled and
maintained at an appropriate quality. One aspect of environmental quality is
the particle content of the air.
HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to
sweep particles away from the filling/closing area and maintain unidirectional
airflow during operations.

Supporting Clean Areas class (1000-100000)

Supporting clean areas can have various classifications and functions. Many
support areas function as zones in which non sterile components, formulated
products, in-process materials, equipment, and container/closures are
prepared, held, or transferred. These environments are soundly designed when
they minimize the level of particle contaminants in the final product and
control the microbiological content (bio burden) of articles and components
that are subsequently sterilized.

The nature of the activities conducted in a supporting clean area determines its
classification:-
 FDA recommends that the area immediately adjacent to the aseptic
processing line meet, at a minimum, Class 10,000 (ISO 7) standards
under dynamic conditions.
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 Manufacturers can also classify this area as Class 1,000 (ISO 6) or

maintain the entire aseptic filling room at Class 100 (ISO 5). An area
classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate
for less critical activities (e.g., equipment cleaning).

Clean Area Separation

To maintain air quality, it is important to achieve a proper airflow from areas of

higher cleanliness to adjacent less clean areas. It is vital for rooms of higher air
cleanliness to have a substantial positive pressure differential relative to
adjacent rooms of lower air cleanliness.
The Agency recommends that pressure differentials between clean rooms be
monitored continuously throughout each shift and frequently recorded. All
alarms should be documented and deviations from established limits should be
investigated.
Air change rate is another important clean room design parameter. For Class
100,000 (ISO 8) supporting rooms, airflow sufficient to achieve at least 20 air
changes per hour is typically acceptable. Significantly higher air change rates
are normally needed for Class 10,000 and Class 100 areas.

2. Air Filtration

i. Membrane

A compressed gas should be of appropriate purity (e.g., free from oil) and its
microbiological and particle quality after filtration should be equal to or better
than that of the air in the environment into which the gas is introduced.
Compressed gases such as air, nitrogen, and carbon dioxide are often used in
cleanrooms and are frequently employed in purging or overlaying.

 Membrane filters can be used to filter a compressed gas to meet an

appropriate high-quality standard. These filters are often used to
produce a sterile compressed gas to conduct operations involving sterile
materials, such as components and equipment. For example, we
recommend that sterile membrane filters be used for autoclave air lines,
lyophilizer vacuum breaks, and tanks containing sterilized materials.
 Gas filters (including vent filters) should be dry. Condensate on a gas
filter can cause blockage during use or allow for the growth of
microorganisms. Use of hydrophobic filters, as well as application of heat
to these filters where appropriate, prevents problematic moisture
residues.

ii. High-Efficiency Particulate Air (HEPA)

 HEPA filter integrity should be maintained to ensure aseptic conditions.

Leak testing should be performed at installation to detect integrity
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breaches around the sealing gaskets, through the frames, or through

various points on the filter media. Thereafter, leak tests should be
performed at suitable time intervals for HEPA filters in the aseptic
processing facility. For example, such testing should be performed twice
a year for the aseptic processing room.
 Additional testing may be appropriate when air quality is found to be
unacceptable, facility renovations might be the cause of disturbances to
ceiling or wall structures, or as part of an investigation into a media fill
or drug product sterility failure.
 Among the filters that should be leak tested are those installed in dry
heat de-pyrogenation tunnels and ovens commonly used to depyrogenate
glass vials. Where justified, alternate methods can be used to test HEPA
filters in the hot zones of these tunnels and ovens.
 There is a major difference between filter leak testing and efficiency
testing. An efficiency test is a general test used to determine the rating of
the filter.8 An intact HEPA filter should be capable of retaining at least
99.97 percent of particulates greater than 0.3 μm in diameter.

3.Design

Other appropriate technologies that achieve increased sterility assurance are

also encouraged.

 Aseptic processes are designed to minimize exposure of sterile articles to

the potential contamination hazards of the manufacturing operation.
Limiting the duration of exposure of sterile product elements, providing the
highest possible environmental control, optimizing process flow, and
designing equipment to prevent entrainment of lower quality air into the
Class 100 (ISO 5) clean area are essential to achieving high assurance of
sterility.
 Both personnel and material flow should be optimized to prevent
unnecessary activities that could increase the potential for introducing
contaminants to exposed product, container-closures, or the surrounding
environment.
 Any intervention or stoppage during an aseptic process can increase the
risk of contamination. The design of equipment used in aseptic processing
should limit the number and complexity of aseptic interventions by
personnel.
 Products should be transferred under appropriate cleanroom conditions.
For example, lyophilization processes include transfer of aseptically filled
product in partially sealed containers.
 The sterile drug product and its container-closures should be protected by
equipment of suitable design.
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 Carefully designed curtains and rigid plastic shields are among the
barriers that can beused in appropriate locations to achieve segregation of
the aseptic processing line. Use of an isolator system further enhances
product protection
 If stoppered vials exit an aseptic processing zone or room prior to capping,
appropriate assurances should be in place to safeguard the product, such
as local protection until completion of the crimping step. Use of devices for
on-line detection of improperly seated stoppers can provide additional
assurance.

4.Personal, Training, Qualification, & Monitoring:

A. Personnel

 A well-designed, maintained, and operated aseptic process minimizes

personnel intervention. As operator activities increase in an aseptic
processing operation, the risk to finished product sterility also increases.
To ensure maintenance of product sterility, it is critical for operators
involved in aseptic activities to use aseptic technique at all times.
 Appropriate training should be conducted before an individual is
permitted to enter the aseptic manufacturing area.

Some of the techniques aimed at maintaining sterility of sterile items and

surfaces include:

 Contact sterile materials only with sterile instruments

 Sterile instruments should always be used in the handling of sterilized

materials
 Sterile instruments should always be used in the handling of sterilized
materials. Between uses, sterile instruments should be held under Class
100 (ISO 5) conditions and maintained in a manner that prevents
contamination (e.g., placed in sterilized containers).
 After initial gowning, sterile gloves should be regularly sanitized or
changed, as appropriate, to minimize the risk of contamination.
Personnel should not directly contact sterile products, containers,
closures, or critical surfaces with any part of their gown or gloves.

 Move slowly and deliberately

Rapid movements can create unacceptable turbulence in a critical area.

 Keep the entire body out of the path of unidirectional airflow

Unidirectional airflow design is used to protect sterile equipment surfaces,
container-closures, and product.
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5. Components and Container/Closures:

Components

 A drug product produced by aseptic processing can become

contaminated through the use of one or more components that are
contaminated with microorganisms or endotoxins.
 Examples of components include active ingredients, Water for Injection
(WFI), and other excipients. It is important to characterize the microbial
content (e.g., bioburden, endotoxin) of each component that could be
contaminated and establish appropriate acceptance limits.
 Endotoxin load data are significant because parenteral products are
intended to be nonpyrogenic. There should be written procedures and
appropriate specifications for acceptance or rejection of each lot of
components that might contain endotoxins. Any components failing to
meet defined endotoxin limits should be rejected.
 Dry heat sterilization is a suitable method for components that are heat
stable and insoluble. However, conducting carefully designed heat
penetration and distribution studies is of particular significance for
powder sterilization because of the insulating effects of the powder.
Irradiation can be used to sterilize some components.

Containers/Closures :

1. Preparation :
 Containers and closures should be rendered sterile and, for parenteral
drug products, nonpyrogenic. The process used will depend primarily on
the nature of the container and/or closure materials. The validation
study for such a process should be adequate to demonstrate its ability to
render materials sterile and non-pyrogenic. Written procedures should
specify the frequency of revalidation of these processes as well as time
limits for holding sterile, depyrogenated containers and closures.
 Pre-sterilization preparation of glass containers usually involves a series
of wash and rinse cycles
 The adequacy of the depyrogenation process can be assessed by spiking
containers and closures with known quantities of endotoxin, followed by
measuring endotoxin content after depyrogenation.
 Plastic containers can be sterilized with an appropriate gas, irradiation,
or other suitable means. For gases such as Ethylene Oxide (EtO), certain
issues should receive attention. For example, the parameters and limits
of the EtO sterilization cycle (e.g., temperature, pressure, humidity, gas
concentration, exposure time, degassing, aeration, and determination of
residuals) should be specified and monitored closely.
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 Rubber closures (e.g., stoppers and syringe plungers) can be cleaned by

multiple cycles of washing and rinsing prior to final steam or irradiation
sterilization.
 At minimum, the initial rinses for the washing process should employ at
least Purified Water, USP, of minimal endotoxin content, followed by final
rinse(s) with WFI for parenteral products. Normally, depyrogenation can
be achieved by multiple rinses of hot WFI.
 Potential source of contamination is the siliconization of rubber stoppers.

2. Inspection of Container Closure System

A container closure system that permits penetration of microorganisms is
unsuitable for a sterile product. Any damaged or defective units should be
detected, and removed, during inspection of the final sealed product.
Safeguards should be implemented to strictly preclude shipment of product
that may lack container closure integrity and lead to nonsterility.

Microbiological Testing Objectives:-

 To review microbiological environmental and quality control testing
 Microbiological Environmental Monitoring
 Container integrity testing
 Pre-sterilization testing.
 Media fill medium growth promotion testing
 Sterility Testing
 Other microbiological laboratory issue

Microbiological testing of water:- Water should also be tested for presence of

coli forms and/or pseudomonas if appropriate (may cause bio film)

Water used for parenterals should be tested for pyrogens – limit is not more
than 0.25 EU/ml. Water should be tested using R2A agar (low nutrient for the
recovery of water borne organisms) incubated for at least 5 days at 30-35°C
Sampling procedures should follow those used in production.

Microbiological testing of Air Sampling Locations:- Should be based on risk

of microbiological contamination , Should be clustered around areas where
product or components are exposed
e.g. at filling heads on filling lines , loading of product into lyophilizers ,
stopper bowls ,where aseptic connections are made ,where there are high levels
of operator activity (but without impacting on production)

Control of microbiological contamination.

(a) Appropriate written procedures, designed to prevent objectionable

microorganisms in drug products not required to be sterile, shall be
established and followed.
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(b) Appropriate written procedures, designed to prevent microbiological

contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include validation of all aseptic and
sterilization processes.

(c) Following stability testing